Methods and compositions for the treatment of autoimmune disorders using clofarabine

ABSTRACT

This invention relates to methods of treating or preventing an autoimmune disorder comprising the administration of clofarabine or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, prodrug or metabolite thereof to a patient in need of such treatment. The invention further relates to methods of treating or preventing an autoimmune disorder comprising the administration of clofarabine or a pharmaceutically acceptable salt, hydrate, solvate, clathrate, prodrug or metabolite thereof and an additional therapeutic agent to a patient in need of such treatment.

This application is a divisional of U.S. application Ser. No. 10/529,519filed Aug. 24, 2005, now abandoned, which is a National StageApplication filed under 35 U.S.C. §371 of PCT/US03/30409 filed Sep. 25,2003, which in turn claims the benefit of U.S. Application No.60/414,687 filed Sep. 27, 2002, the contents of all of which are herebyincorporated herein by reference for all purposes.

1. FIELD OF THE INVENTION

This invention relates to pharmaceutical compositions, dosage forms anddosage regimens utilizing clofarabine. This invention also relates tomethods of treating autoimmune disorders, and to methods for dosingclofarabine, each of these methods also encompasses reducing or avoidingundesired effects associated with conventional treatment of autoimmunedisorders.

2. BACKGROUND OF THE INVENTION 2.1 Autoimmune Disorders

The immune system is a complicated network of cells and cell componentsthat defend the body and eliminate infections caused by bacteria,viruses, and other invading microbes. Autoimmune disorders, however,cause the immune system to mistakenly attack the cells, tissues, andorgans of a patient's own body.

There are many different autoimmune diseases, and they can each affectthe body in different ways. Autoimmune disorders can target specificorgans and tissues in the body, e.g., the brain, as in MultipleSclerosis, or the gastrointestinal system as in Crohn's disease. Inother cases, autoimmune disorders can affect a variety of tissues in thesame patient or from patient to patient. Additionally, autoimmunedisorders can have permanent effects on the body, such as in the causalrole of Type I, insulin dependent diabetes.

Some autoimmune diseases are known to begin or worsen with certaintriggers such as viral infections. It is important to be aware of thefactors that can be avoided to help prevent or minimize the amount ofdamage from the autoimmune disease. Other less understood influencesaffecting the immune system and the course of autoimmune diseasesinclude aging, chronic stress, hormones and pregnancy.

Traditional medications slow or suppress the immune system response inan attempt to stop the inflammation involved in the autoimmune attack.For example, medication can slow or stop the immune system's destructionof the kidneys or joints. These drugs include corticosteroids(prednisone), methotrexate, cyclophosphamide, azathioprine, andcyclosporins. Unfortunately, these medications also suppress the abilityof the immune system to fight infection and have other potentiallyserious side effects.

A current goal in caring for patients with autoimmune diseases is tofind treatments that produce remissions with fewer side effects.

2.2 Clofarabine

Purine nucleosides have been previously reported as useful for thetreatment of cancers. An exemplary class of purine nucleosides and theirpotential use in anti-cancer therapy is disclosed in U.S. Pat. Nos.4,751,221 and 4,918,179. Subsequently, the specific nucleosidesfludarabine and clofarabine and their proposed utility as cytotoxiccompounds were described in U.S. Pat. Nos. 5,304,514; 5,384,310 and5,661,136.

Clofarabine is an adenosine nucleoside analogue which is chemicallynamed 2 Chloro 9 (2 deoxy 2 fluoro β D arabinofuranosyl)adenine[CL-F-Ara-A]. Shortnacy Fowler A T, Tiwari K N, Montgomery J A, et al.Synthesis and biological activity of 4′ C hydroxymethyl 2′ fluoro Darabinofuranosylpurine nucleosides. Nucleosides Nucleotides NucleicAcids 20(8):1583 98, 2001.

Clofarabine appears to have multiple mechanisms of action againstcancer, including inhibiting both DNA polymerases and ribonucleotidereductase and inducing apoptosis. It also appears to be effectiveagainst certain cancers through a unique additional mechanism, wherebyit directly damages the mitochondria in cancer cells and inducesapoptosis (Genini D, Adachi S, Chao Q, et al. Blood 2000 96: 3537).

Clofarabine is also known by the tradename CLOFAREX, and is beingdeveloped for the acute treatment of myelogenous leukemia in adults, foracute lymphocytic leukemia in children and for the treatment of advancedsolid tumors in adults. Johnson S A. Nucleoside analogues in thetreatment of hematological malignancies. Expert Opin Pharmacother2(6):929-43, 2001.

Recently, certain nucleoside analogs have been reported to havepotential utility at low doses (0.04 to about 0.20 mg/kg/day) intreating autohemyltic anemia (U.S. Pat. No. 5,106,837); rheumatoidarthritis (U.S. Pat. No. 5,310,732); and inflammatory Bowel Disease(U.S. Pat. No. 5,506,213). Furthermore, a class of nucleoside analogshave been reported to have potential utility in the treatment ofmultiple sclerosis at doses from about 0.04 to about 0.20 mg/kg per day(U.S. Pat. No. 5,506,214).

Clofarabine is an interesting anticancer drug candidate. However, all ofthe potential uses for clofarabine have thus far remained unexplored orundeveloped. Further, there remains a need for high dosage compositions.Also, as discussed above, treatments for autoimmune disorders areneeded. Finally, dosing regimens, particularly for the use ofclofarabine in the treatment of diseases other than cancer are needed.

3. SUMMARY OF THE INVENTION

This invention encompasses compositions comprising, and methods ofusing, clofarabine, and pharmaceutically acceptable salts,stereoisomers, solvates, hydrates and clathrates thereof.

A first embodiment of the invention encompasses a method of treating,preventing or managing an autoimmune disorder which comprisesadministering to a patient in need of such treatment a therapeuticallyor prophylactively effective amount of clofarabine or a pharmaceuticallyacceptable salt, solvate, hydrate, or clathrate thereof. In a specificembodiment of the invention, the autoimmune disorder is a disorder ofthe nervous system, the blood, the gastrointestinal system, theendocrine glands, the skin, the musculoskeletal system, the connectivetissue or combinations thereof. Significantly, the invention encompassesnovel doses and dosing regimens for treating autoimmune disorders. Inparticular, doses higher than those previously contemplated in the artare used chronically or periodically and in cycling therapy to treat orprevent autoimmune disorders. A preferred embodiment is to treatmultiple sclerosis with doses higher than previously contemplated in theart.

In a preferred embodiment, the invention encompasses the treatment,prevention or management of certain specific autoimmune disordersincluding, but not limited to, Alopecia Areata, Ankylosing Spondylitis,Antiphospholipid Syndrome, Autoimmune Addison's Disease, AutoimmuneHemolytic Anemia, Autoimmune Hepatitis, Autoimmune Uveitis, AutoimmuneOophoritis, Autoimmune Orchitis, Behcet's Disease, Bullous Pemphigoid,Cardiomyopathy, Celiac Sprue-Dermatitis, Chronic Fatigue ImmuneDysfunction Syndrome (CFIDS), Chronic Inflammatory DemyelinatingPolyneuropathy, Churg-Strauss Syndrome, Cicatricial Pemphigoid, CRESTSyndrome, Cold Agglutinin Disease, Crohn's Disease, DermatitisHerpetiformis, Essential Mixed Cryoglobulinemia,Fibromyalgia-Fibromyositis, Graves' Disease, Guillain-Barré, Hashimoto'sThyroiditis, Idiopathic Pulmonary Fibrosis, Idiopathic ThrombocytopeniaPurpura (ITP), IgA Nephropathy, Insulin dependent Diabetes, ImmuneMediated Diabetes, Juvenile Arthritis, Lichen Planus, Ménière's Disease,Mixed Connective Tissue Disease, Myasthenia Gravis, Pemphigus Vulgaris,Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, PolyglandularSyndromes, Polymyalgia Rheumatica, Polymyositis and Dermatomyositis,Primary Agammag-lobulinemia, Primary Biliary Cirrhosis, Psoriasis,Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever, Sarcoidosis,Scleroderma, Sjögren's Syndrome, Stiff-Man Syndrome, Takayasu Arteritis,Temporal Arteritis, Giant Cell Arteritis, Ulcerative Colitis, Uveitis,Vasculitis, Vitiligo or Wegener's Granulomatosis.

In a preferred embodiment, the multiple sclerosis is relapsing-remittingmultiple sclerosis or secondary progressive multiple sclerosis.

In another preferred embodiment, the patient to be treated is a human,including adults, adolescents, children, and infants.

A second embodiment of the invention encompasses a method of treating,preventing or managing an autoimmune disorder comprising administeringto a patient in need of such treatment a therapeutically orprophylactively effective amount of clofarabine or a pharmaceuticallyacceptable salt, solvate, hydrate, or clathrate thereof and anadditional therapeutic agent. In a preferred embodiment, the additionaltherapeutic agent is an antibiotic, an antiemetic agent, anantidepressant, and antifungal agent, an antiinflammatory agent, anantiviral agent, an immunomodulatory agent, a β-Interferon, analkylating agent, a hormone or a cytokine.

A third embodiment of the invention encompasses a method of reducing oravoiding adverse effects of traditional therapies for autoimmunedisorders which comprises administering to a patient in need of suchrelief a therapeutically or prophylactively effective amount ofclofarabine or a pharmaceutically acceptable salt, solvate, hydrate, orclathrate thereof. Examples of adverse effects include, but are notlimited to, nausea, reversible kidney dysfunction, depression, herpeszoster infection and skin rash.

Similarly, the dosing regimens avoid or reduce the side or adverse orunwanted effects associated with the administration of purine nucleosideanalogues such as fludarabine and cladribine.

3.1 Definitions

As used herein, the term “patient” means an animal (e.g., cow, horse,sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guineapig, etc.), preferably a mammal such as a non-primate and a primate(e.g., monkey and human), most preferably a human. In certainembodiments, the patient is an infant, child, adolescent or adult.

As used herein, a “therapeutically effective amount” refers to thatamount of the compound of the invention or other active ingredientsufficient to provide a therapeutic benefit in the treatment ormanagement of the disease or to delay or minimize symptoms associatedwith the disease. Further, a therapeutically effective amount withrespect to a compound of the invention means that amount of therapeuticagent alone, or in combination with other therapies, that provides atherapeutic benefit in the treatment or management of the disease. Usedin connection with an amount of a compound of the invention, the termcan encompass an amount that improves overall therapy, reduces or avoidssymptoms or causes of disease, or enhances the therapeutic efficacy ofor synergies with another therapeutic agent.

As used herein, a “prophylactically effective amount” refers to thatamount of a compound of the invention or other active ingredientsufficient to result in the prevention, recurrence or spread of thedisease. A prophylactically effective amount may refer to the amountsufficient to prevent initial disease or the recurrence or spread of thedisease or the occurrence of the disease in a patient, including but notlimited to those predisposed to the disease. A prophylacticallyeffective amount may also refer to the amount that provides aprophylactic benefit in the prevention of the disease. Further, aprophylactically effective amount with respect to a compound of theinvention means that amount alone, or in combination with other agents,that provides a prophylactic benefit in the prevention of the disease.Used in connection with an amount of a compound of the invention, theterm can encompass an amount that improves overall prophylaxis orenhances the prophylactic efficacy of or synergies with anotherprophylactic agent.

As used herein, a “therapeutic protocol” refers to a regimen of timingand dosing of one or more therapeutic agents.

As used herein, a “prophylactic protocol” refers to a regimen of timingand dosing of one or more prophylactic agents.

A used herein, a “protocol” includes dosing schedules and dosingregimens. As used herein, “in combination” refers to the use of morethan one prophylactic and/or therapeutic agents.

As used herein, the terms “manage”, “managing” and “management” refer tothe beneficial effects that a subject derives from a prophylactic ortherapeutic agent, which does not result in a cure of the disease. Incertain embodiments, a subject is administered one or more prophylacticor therapeutic agents to “manage” a disease so as to prevent theprogression or worsening of the disease.

As used herein, the terms “prevent”, “preventing” and “prevention” referto the prevention of the onset recurrence, spread or of the disease in asubject resulting from the administration of a prophylactic ortherapeutic agent.

As used herein, the terms “treat”, “treating” and “treatment” refer tothe eradication or amelioration of the disease or symptoms associatedwith the disease. In certain embodiments, such terms refer to minimizingthe spread or worsening of the disease resulting from the administrationof one or more prophylactic or therapeutic agents to a subject with sucha disease.

As used herein, the term “pharmaceutically acceptable salts” refer tosalts prepared from pharmaceutically acceptable non-toxic acids or basesincluding inorganic acids and bases and organic acids and bases.Suitable pharmaceutically acceptable base addition salts for thecompound of the present invention include, but are not limited to,metallic salts made from aluminum, calcium, lithium, magnesium,potassium, sodium and zinc or organic salts made from lysine,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Suitablenon-toxic acids include, but are not limited to, inorganic and organicacids such as acetic, alginic, anthranilic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, formic, fumaric, furoic,galacturonic, gluconic, glucuronic, glutamic, glycolic, hydrobromic,hydrochloric, isethionic, lactic, maleic, malic, mandelic,methanesulfonic, mucic, nitric, pamoic, pantothenic, phenylacetic,phosphoric, propionic, salicylic, stearic, succinic, sulfanilic,sulfuric, tartaric acid, and p-toluenesulfonic acid. Specific non-toxicacids include hydrochloric, hydrobromic, phosphoric, sulfuric, andmethanesulfonic acids. Examples of specific salts thus includehydrochloride and mesylate salts.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide anactive compound, particularly a compound of the invention. Examples ofprodrugs include, but are not limited to, derivatives and metabolites ofa compound of the invention that include biohydrolyzable moieties suchas biohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogues. Preferably, prodrugs of compoundswith carboxyl functional groups are the lower alkyl esters of thecarboxylic acid. The carboxylate esters are conveniently formed byesterifying any of the carboxylic acid moieties present on the molecule.Prodrugs can typically be prepared using well-known methods, such asthose described by Burger's Medicinal Chemistry and Drug Discovery 6thed. (Donald J. Abraham ed., 2001, Wiley) and Design and Application ofProdrugs (H. Bundgaard ed., 1985, Harwood Academic Publishers Gmfh).

As used herein and unless otherwise indicated, the terms“biohydrolyzable amide,” “biohydrolyzable ester,” “biohydrolyzablecarbamate,” “biohydrolyzable carbonate,” “biohydrolyzable ureide,”“biohydrolyzable phosphate” mean an amide, ester, carbamate, carbonate,ureide, or phosphate, respectively, of a compound that either: 1) doesnot interfere with the biological activity of the compound but canconfer upon that compound advantageous properties in vivo, such asuptake, duration of action, or onset of action; or 2) is biologicallyinactive but is converted in vivo to the biologically active compound.Examples of biohydrolyzable esters include, but are not limited to,lower alkyl esters, alkoxyacyloxy esters, alkyl acylamino alkyl esters,and choline esters. Examples of biohydrolyzable amides include, but arenot limited to, lower alkyl amides, α-amino acid amides, alkoxyacylamides, and alkylaminoalkylcarbonyl amides. Examples of biohydrolyzablecarbamates include, but are not limited to, lower alkylamines,substituted ethylenediamines, aminoacids, hydroxyalkylamines,heterocyclic and heteroaromatic amines, and polyether amines.

As used herein and unless otherwise indicated, the term “metabolite”means the product of metabolism of a compound of the invention, e.g., ametabolite is a compound formed by hydrolysis, oxidation, or other invivo reaction, particularly in the liver. In other words, the inventioncontemplates the synthesis and administration of compounds that are invivo metabolites of clofarabine. Examples of metabolites include, butare not limited to, derivatives of a compound of the invention thatinclude biohydrolyzable moieties such as biohydrolyzable amides,biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzablecarbonates, biohydrolyzable ureides, and biohydrolyzable phosphateanalogues. Preferably, metabolites of compounds of the invention aremonophosphates, diphosphates and triphosphates, more preferablytriphosphates.

As used herein and unless otherwise indicated, the term “optically pure”or “stereomerically pure” means a composition that comprises onestereoisomer of a compound and is substantially free of otherstereoisomers of that compound. For example, a stereomerically purecomposition of a compound having one chiral center will be substantiallyfree of the opposite enantiomer of the compound. Furthermore, the sugarmoiety of the nucleoside analog can exist in either the D or L forms ofthe sugar. As such, for example, a stereomerically pure composition of aD compound will be substantially free of the L form of the compound. Astereomerically pure composition of a compound having two chiral centerswill be substantially free of other diastereomers of the compound. Atypical stereomerically pure compound comprises greater than about 80%by weight of one stereoisomer of the compound and less than about 20% byweight of other stereoisomers of the compound, more preferably greaterthan about 90% by weight of one stereoisomer of the compound and lessthan about 10% by weight of the other stereoisomers of the compound,even more preferably greater than about 95% by weight of onestereoisomer of the compound and less than about 5% by weight of theother stereoisomers of the compound, and most preferably greater thanabout 97% by weight of one stereoisomer of the compound and less thanabout 3% by weight of the other stereoisomers of the compound.

As used herein and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center.

As used herein, the term “connective tissue” means tissue in the bodythat maintains the form of the body and its organs and provides cohesionand internal support, such as bone, ligaments, tendons, cartilage,adipose tissue, and aponeuroses.

4. DETAILED DESCRIPTION OF THE INVENTION 4.1 The Compound of theInvention Clofarabine

The invention encompasses the use of clofarabine in the methods,compositions and dosage forms described herein. It should be recognizedby one of skill in the art that the invention encompassespharmaceutically acceptable salts, hydrates, clathrates, polymorphs,prodrugs, and stereoisomers of clofarabine, including both the D and Lisomers of the sugar moeity as well as metabolites. Clofarabine isreadily prepared using the methods in U.S. Pat. Nos. 5,034,518,5,384,310, and 5,661,136 which are incorporated herein by reference.Alternatively, clofarabine is commercially available and can bepurchased.

Stereochemically pure compounds can be obtained from the racemiccompound by techniques known in the art. Examples include, but are notlimited to, the formation of chiral salts and the use of chiral or highperformance liquid chromatography “HPLC” and the formation andcrystallization of chiral salts. See, e.g., Jacques, J., et al.,Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York,1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L.,Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen,S. H., Tables of Resolving Agents and Optical Resolutions p. 268 (E. L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind., 1972).

Prodrugs and metabolites of Clofarabine can be readily produced bymethods well known in the art such as those described by Burger'sMedicinal Chemistry and Drug Discovery 6th ed. (Donald J. Abraham ed.,2001, Wiley) and Design and Application of Prodrugs (H. Bundgaard ed.,1985, Harwood Academic Publishers Gmfh). Particular metabolites ofclofarabine encompassed by the invention are clofarabine phosphate,clofarabine diphosphate and clofarabine triphosphate. In a preferredembodiment of the invention, the metabolite is clofarabine triphosphate.

4.2 Methods of Use

The invention encompasses methods of treating, preventing or managingautoimmune diseases or disorders in a patient which compriseadministering to a patient in need of such treatment or prevention atherapeutically effective amount of clofarabine, or a pharmaceuticallyacceptable prodrug, stereoisomer, salt, solvate, hydrate, or clathratethereof.

Autoimmune disorders within the scope of the methods of the inventionare those which target the nervous system, the blood, thegastrointestinal system, the endocrine glands, the skin, themusculoskeletal system, the connective tissue or combinations thereof.Specific autoimmune diseases or disorders within the scope of themethods of the invention are: Alopecia Areata, Ankylosing Spondylitis,Antiphospholipid Syndrome, Autoimmune Addison's Disease, AutoimmuneHemolytic Anemia, Autoimmune Hepatitis, Autoimmune Uveitis, AutoimmuneOophoritis, Autoimmune Orchitis, Behcet's Disease, Bullous Pemphigoid,Cardiomyopathy, Celiac Sprue-Dermatitis, Chronic Fatigue ImmuneDysfunction Syndrome (CFIDS), Chronic Inflammatory DemyelinatingPolyneuropathy, Churg-Strauss Syndrome, Cicatricial Pemphigoid, CRESTSyndrome, Cold Agglutinin Disease, Crohn's Disease, DermatitisHerpetiformis, Essential Mixed Cryoglobulinemia,Fibromyalgia-Fibromyositis, Graves' Disease, Guillain-Barré, Hashimoto'sThyroiditis, Idiopathic Pulmonary Fibrosis, Idiopathic ThrombocytopeniaPurpura (ITP), IgA Nephropathy, Insulin dependent Diabetes, ImmuneMediated Diabetes, Juvenile Arthritis, Lichen Planus, Ménière's Disease,Mixed Connective Tissue Disease, Myasthenia Gravis, Pemphigus Vulgaris,Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, PolyglandularSyndromes, Polymyalgia Rheumatica, Polymyositis and Dermatomyositis,Primary Agammag-lobulinemia, Primary Biliary Cirrhosis, Psoriasis,Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever, Sarcoidosis,Scleroderma, Sjögren's Syndrome, Stiff-Man Syndrome, Takayasu Arteritis,Temporal Arteritis, Giant Cell Arteritis, Ulcerative Colitis, Uveitis,Vasculitis, Vitiligo or Wegener's Granulomatosis.

In other embodiments, diseases to be treated or prevented byadministering to a patient in need thereof an effective amount ofclofarabine include Alopecia Areata, Ankylosing Spondylitis,Antiphospholipid Syndrome, Autoimmune Addison's Disease, AutoimmuneHemolytic Anemia, Autoimmune Hepatitis, Autoimmune Uveitis, AutoimmuneOophoritis, Autoimmune Orchitis, Behcet's Disease, Bullous Pemphigoid,Cardiomyopathy, Celiac Sprue-Dermatitis, Chronic Fatigue ImmuneDysfunction Syndrome (CFIDS), Chronic Inflammatory DemyelinatingPolyneuropathy, Churg-Strauss Syndrome, Cicatricial Pemphigoid, CRESTSyndrome, Cold Agglutinin Disease, Crohn's Disease, DermatitisHerpetiformis, Essential Mixed Cryoglobulinemia,Fibromyalgia-Fibromyositis, Graves' Disease, Guillain-Barré, Hashimoto'sThyroiditis, Idiopathic Pulmonary Fibrosis, Idiopathic ThrombocytopeniaPurpura (ITP), IgA Nephropathy, Insulin dependent Diabetes, ImmuneMediated Diabetes, Juvenile Arthritis, Lichen Planus, Ménière's Disease,Mixed Connective Tissue Disease, Myasthenia Gravis, Pemphigus Vulgaris,Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, PolyglandularSyndromes, Polymyalgia Rheumatica, Polymyositis and Dermatomyositis,Primary Agammag-lobulinemia, Primary Biliary Cirrhosis, Psoriasis,Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever, Sarcoidosis,Scleroderma, Sjögren's Syndrome, Stiff-Man Syndrome, Takayasu Arteritis,Temporal Arteritis, Giant Cell Arteritis, Ulcerative Colitis, Uveitis,Vasculitis, Vitiligo or Wegener's Granulomatosis.

In preferred embodiments of the invention, the multiple sclerosis isrelapsing-remitting multiple sclerosis or secondary progressive multiplesclerosis.

Specific methods of the invention further comprise the administration ofan additional therapeutic agent (i.e. a therapeutic agent other than acompound of the invention) In certain embodiments of the presentinvention, the compounds of the invention can be used in combinationwith at least one other therapeutic agent. Therapeutic agents include,but are not limited to antibiotics, antiemetic agents, antidepressants,and antifungal agents, antiinflammatory agents, antiviral agents,immunomodulatory agents, β-interferons, alykylating agents, hormones orcytokines.

In certain embodiments, clofarabine can be administered or formulated incombination with antibiotics. In certain embodiments, the antibiotic isa macrolide (e.g., tobramycin (Tobi®)), a cephalosporin (e.g.,cephalexin (Keflex®), cephradine (Velosef®), cefuroxime (Ceftin®)),cefprozil (Cefzil®)), cefaclor (Ceclor®), cefixime (Suprax®) orcefadroxil (Duricef®)), a clarithromycin (e.g. clarithromycin(Biaxin®)), an erythromycin (e.g., erythromycin (EMycin®)), a penicillin(e.g., penicillin V (V-Cillin K® or Pen Vee K®)) or a quinolone (e.g.,ofloxacin (Floxin®), ciprofloxacin (Cipro®) or norfloxacin (Noroxin®)),aminoglycoside antibiotics (e.g., apramycin, arbekacin, bambermycins,butirosin, dibekacin, neomycin, neomycin, undecylenate, netilmicin,paromomycin, ribostamycin, sisomicin, and spectinomycin), amphenicolantibiotics (e.g., azidamfenicol, chloramphenicol, florfenicol, andthiamphenicol), ansamycin antibiotics (e.g., rifamide and rifampin),carbacephems (e.g., loracarbef), carbapenems (e.g., biapenem andimipenem), cephalosporins (e.g., cefaclor, cefadroxil, cefamandole,cefatrizine, cefazedone, cefozopran, cefpimizole, cefpiramide, andcefpirome), cephamycins (e.g., cefbuperazone, cefmetazole, andcefminox), monobactams (e.g., aztreonam, carumonam, and tigemonam),oxacephems (e.g., flomoxef, and moxalactam), penicillins (e.g.,amdinocillin, amdinocillin pivoxil, amoxicillin, bacampicillin,benzylpenicillinic acid, benzylpenicillin sodium, epicillin,fenbenicillin, floxacillin, penamccillin, penethamate hydriodide,penicillin o-benethamine, penicillin 0, penicillin V, penicillin Vbenzathine, penicillin V hydrabamine, penimepicycline, andphencihicillin potassium), lincosamides (e.g., clindamycin, andlincomycin), macrolides (e.g., azithromycin, carbomycin, clarithomycin,dirithromycin, erythromycin, and erylromycin acistrate), amphomycin,bacitracin, capreomycin, colistin, enduracidin, enviomycin,tetracyclines (e.g., apicycline, chlortetracycline, clomocycline, anddemeclocycline), 2,4-diaminopyrimidines (e.g., brodimoprim), nitrofurans(e.g., furaltadone, and furazolium chloride), quinolones and analogsthereof (e.g., cinoxacin, ciprofloxacin, clinafloxacin, flumequine, andgrepagloxacin), sulfonamides (e.g., acetyl sulfamethoxypyrazine,benzylsulfamide, noprylsulfamide, phthalylsulfacetamide,sulfachrysoidine, and sulfacytine), sulfones (e.g., diathymosulfone,glucosulfone sodium, and solasulfone), cycloserine, mupirocin andtuberin.

In certain embodiments, clofarabine can be administered or formulated incombination with an antiemetic agent. Suitable antiemetic agentsinclude, but are not limited to, metoclopromide, domperidone,prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,ondansetron, granisetron, hydroxyzine, acethylleucine monoethanolamine,alizapride, azasetron, benzquinamide, bietanautine, bromopride,buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl,pipamazine, scopolamine, sulpiride, tetrahydrocannabinols,thiethylperazine, thioproperazine, tropisetron, and mixtures thereof.

In certain embodiments, clofarabine can be administered or formulated incombination with an antidepressant. Suitable antidepressants include,but are not limited to, binedaline, caroxazone, citalopram, dimethazan,fencamine, indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotinine, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, moclobemide, nefazodone, oxaflozane, piberaline,prolintane, pyrisuccideanol, ritanserin, roxindole, rubidium chloride,sulpirde, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

In certain embodiments, clofarabine can be administered or formulated incombination with an antifungal agent. Suitable antifungal agents includebut are not limited to amphotericin B, itraconazole, ketoconazole,fluconazole, intrathecal, flucytosine, miconazole, butoconazole,clotrimazole, nystatin, terconazole, tioconazole, ciclopirox, econazole,haloprogrin, naftifine, terbinafine, undecylenate, and griseofuldin.

In certain embodiments, clofarabine can be administered or formulated incombination with an antiinflammatory agent. Useful anti-inflammatoryagents include, but are not limited to, non-steroidal anti-inflammatorydrugs such as salicylic acid, acetylsalicylic acid, methyl salicylate,diflunisal, salsalate, olsalazine, sulfasalazine, acetaminophen,indomethacin, sulindac, etodolac, mefenamic acid, meclofenamate sodium,tolmetin, ketorolac, dichlofenac, ibuprofen, naproxen, naproxen sodium,fenoprofen, ketoprofen, flurbinprofen, oxaprozin, piroxicam, meloxicam,ampiroxicam, droxicam, pivoxicam, tenoxicam, nabumetome, phenylbutazone,oxyphenbutazone, antipyrine, aminopyrine, apazone and nimesulide;leukotriene antagonists including, but not limited to, zileuton,aurothioglucose, gold sodium thiomalate and auranofin; and otheranti-inflammatory agents including, but not limited to, methotrexate,colchicine, allopurinol, probenecid, sulfinpyrazone and benzbromarone.

In certain embodiments, clofarabine can be administered or formulated incombination with an antiviral agent. Useful antiviral agents include,but are not limited to, nucleoside analogs, such as zidovudine,acyclovir, gangcyclovir, vidarabine, idoxuridine, trifluridine, andribavirin, as well as foscarnet, amantadine, rimantadine, saquinavir,indinavir, ritonavir, and the alpha-interferons.

Examples of immunomodulatory agents include, but are not limited to,methotrexate, leflunomide, cyclophosphamide, cyclosporine A, macrolideantibiotics (e.g., FK506 (tacrolimus)), methylprednisolone (MP),corticosteroids, steroids, mycophenolate mofetil, rapamycin (sirolimus),mizoribine, deoxyspergualin, brequinar, malononitriloamindes (e.g.,leflunamide), T cell receptor modulators, and cytokine receptormodulators.peptide mimetics, and antibodies (e.g., human, humanized,chimeric, monoclonal, polyclonal, Fvs, ScFvs, Fab or F(ab)2 fragments orepitope binding fragments), nucleic acid molecules (e.g., antisensenucleic acid molecules and triple helices), small molecules, organiccompounds, and inorganic compounds. In particular, immunomodulatoryagents include, but are not limited to, methotrexate, leflunomide,cyclophosphamide, cytoxan, Immuran, cyclosporine A, minocycline,azathioprine, antibiotics (e.g., FK506 (tacrolimus)), methylprednisolone(MP), corticosteroids, steroids, mycophenolate mofetil, rapamycin(sirolimus), mizoribine, deoxyspergualin, brequinar,malononitriloamindes (e.g., leflunamide), T cell receptor modulators,and cytokine receptor modulators.

Examples of T cell receptor modulators include, but are not limited to,anti-T cell receptor antibodies (e.g., anti-CD4 antibodies (e.g.,cM-T412 (Boeringer), IDEC-CE9.1 (IDEC and SKB), mAB 4162W94, Orthocloneand OKTcdr4a (Janssen-Cilag)), anti-CD3 antibodies (e.g., Nuvion(Product Design Labs), OKT3 (Johnson & Johnson), or Rituxan (IDEC)),anti-CD5 antibodies (e.g., an anti-CD5 ricin-linked immunoconjugate),anti-CD7 antibodies (e.g., CHH-380 (Novartis)), anti-CD8 antibodies,anti-CD40 ligand monoclonal antibodies (e.g., IDEC-131 (IDEC)),anti-CD52 antibodies (e.g., CAMPATH 1H (Ilex)), anti-CD2 antibodies,anti-CD11a antibodies (e.g., Xanelim (Genentech)), and anti-B7antibodies (e.g., IDEC-114) (IDEC))) and CTLA4-immunoglobulin. In aspecific embodiment, a T cell receptor modulator is a CD2 antagonist. Inother embodiments, a T cell receptor modulator is not a CD2 antagonist.In another specific embodiment, a T cell receptor modulator is a CD2binding molecule, preferably MEDI-507. In other embodiments, a T cellreceptor modulator is not a CD2 binding molecule.

Examples of cytokine receptor modulators include, but are not limitedto, soluble cytokine receptors (e.g., the extracellular domain of aTNF-αreceptor or a fragment thereof, the extracellular domain of anIL-1β receptor or a fragment thereof, and the extracellular domain of anIL-6 receptor or a fragment thereof), cytokines or fragments thereof(e.g., interleukin (IL)-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9,IL-10, IL-11, IL-12, IL-15, TNF-α, TNF-β, interferon (IFN)-α, IFN-β,IFN-γ, and GM-CSF), anti-cytokine receptor antibodies (e.g., anti-IFNreceptor antibodies, anti-IL-2 receptor antibodies (e.g., Zenapax(Protein Design Labs)), anti-IL-4 receptor antibodies, anti-IL-6receptor antibodies, anti-IL-10 receptor antibodies, and anti-IL-12receptor antibodies), anti-cytokine antibodies (e.g., anti-IFNantibodies, anti-TNF-α antibodies, anti-IL-1β antibodies, anti-IL-6antibodies, anti-IL-8 antibodies (e.g., ABX-IL-8 (Abgenix)), andanti-IL-12 antibodies). In a specific embodiment, a cytokine receptormodulator is IL-4, IL-10, or a fragment thereof. In another embodiment,a cytokine receptor modulator is an anti-IL-1β antibody, anti-IL-6antibody, anti-IL-12 receptor antibody, or anti-TNF-α antibody. Inanother embodiment, a cytokine receptor modulator is the extracellulardomain of a TNF-α receptor or a fragment thereof. In certainembodiments, a cytokine receptor modulator is not a TNF-α antagonist.

In a preferred embodiment, proteins, polypeptides or peptides (includingantibodies) that are utilized as immunomodulatory agents are derivedfrom the same species as the recipient of the proteins, polypeptides orpeptides so as to reduce the likelihood of an immune response to thoseproteins, polypeptides or peptides. In another preferred embodiment,when the subject is a human, the proteins, polypeptides, or peptidesthat are utilized as immunomodulatory agents are human or humanized.

Examples of cytokines include, but are not limited to, interleukin-2(IL-2), interleukin-3 (IL-3), interleukin-4 (IL-4), interleukin-5(IL-5), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-9(IL-9), interleukin-10 (IL-10), interleukin-12 (IL-12), interleukin 15(IL-15), interleukin 18 (IL-18), platelet derived growth factor (PDGF),erythropoietin (Epo), epidermal growth factor (EGF), fibroblast growthfactor (FGF), granulocyte macrophage stimulating factor (GM-CSP),granulocyte colony stimulating factor (G-CSF), macrophage colonystimulating factor (M-CSF), prolactin, and interferon (IFN), e.g.,IFN-alpha, and IFN-gamma).

Examples of hormones include, but are not limited to, luteinizinghormone releasing hormone (LHRH), growth hormone (GH), growth hormonereleasing hormone, ACTH, somatostatin, somatotropin, somatomedin,parathyroid hormone, hypothalamic releasing factors, insulin, glucagon,enkephalins, vasopressin, calcitonin, heparin, low molecular weightheparins, heparinoids, synthetic and natural opioids, insulin thyroidstimulating hormones, and endorphins.

Examples of β-interferons include, but are not limited to, interferonbeta-1a and interferon beta1-b.

Examples of alkylating agents include, but are not limited to nitrogenmustards, ethylenimines, methylmelamines, alkyl sulfonates,nitrosoureas, triazenes, mechlorethamine, cyclophosphamide, ifosfamide,melphalan, chlorambucil, hexamethylmelaine, thiotepa, busulfan,carmustine, streptozocin, dacarbazine and temozolomide.

Clofarabine and the other therapeutics agent can act additively or, morepreferably, synergistically. In a preferred embodiment, a compositioncomprising a compound of the invention is administered concurrently withthe administration of another therapeutic agent, which can be part ofthe same composition or in a different composition from that comprisingthe compounds of the invention. In another embodiment, a compound of theinvention is administered prior to or subsequent to administration ofanother therapeutic agent.

4.3 Doses and Dosage Forms

The magnitude of a prophylactic or therapeutic dose of clofarabine or apharmaceutically acceptable salt, solvate, hydrate, clathrate, prodrug,metabolite or stereoisomer thereof in the acute or chronic management ofa disease or condition will vary, however, with the nature and severityof the disease or condition, and the route by which the activeingredient is administered. The dose, and perhaps the dose frequency,will also vary according to the disease to be treated, the age, bodyweight, and response of the individual patient. Suitable dosing regimenscan be readily selected by those skilled in the art with dueconsideration of such factors. In one embodiment, the dose ofclofarabine is greater than about 0.04 mg/kg/day, preferably greaterthan 0.20 mg/kg/day, most preferably greater than 1 mg/kg/day. Ingeneral, the recommended daily dose range for the conditions describedherein lie within the range of from about 1.25 mg/kg to about 80 mg/kgper day, given as a single once-a-day dose, preferably as divided dosesthroughout a day. Additionally, the recommended daily dose ran can beadministered in cycles as single agents or in combination with othertherapeutic agents. In one embodiment, the daily dose is administered ina single dose or in equally divided doses. Specifically, a daily doserange should be from about 5 mg/kg to about 75 mg/kg per day, morespecifically, between about 20 mg/kg and about 60 mg/kg per day, mostspecifically between about 40 mg/kg and 50 mg/kg per day. In managingthe patient, the therapy should be initiated at a lower dose, perhapsabout 1.25 mg/kg to about 25 mg/kg per day, and increased if necessaryup to about 40 mg/kg to about 50 mg/kg per day as either a single doseor divided doses, depending on the patient's global response. In thetreatment of chronic diseases and disorders, the recommended daily doserange for the conditions described herein lie within the range of fromabout 1.25 mg/kg to about 10 mg/kg per day, given as a single once-a-daydose, preferably as divided doses throughout a day. Specifically, adaily dose range for chronic conditions should be from about 2 mg/kg toabout 6 mg/kg per day, more specifically, between about 4 mg/kg andabout 5 mg/kg per day.

It may be necessary to use dosages of the active ingredient outside theranges disclosed herein in some cases, as will be apparent to those ofordinary skill in the art, but the dosage should not fall below 1.0mg/kg/day. The maximum tolerated doses of clofarabine is approximately80 mg/kg per day. Furthermore, it is noted that the clinician ortreating physician will know how and when to interrupt, adjust, orterminate therapy in conjunction with individual patient response.

Different therapeutically effective amounts may be applicable fordifferent diseases and conditions, as will be readily known by those ofordinary skill in the art. Similarly, amounts sufficient to treat orprevent such diseases, but insufficient to cause, or sufficient toreduce, adverse effects associated with conventional therapies are alsoencompassed by the above described dosage amounts and dose frequencyschedules.

In a preferred embodiment, the invention encompasses a method fortreating, preventing, or managing multiple sclerosis utilizing doseshigher than 1 mg/kg per day, preferably higher than 1.25 mg/kg per day.

4.4 Pharmaceutical Compositions

Pharmaceutical compositions and single unit dosage forms comprisingclofarabine, or a pharmaceutically acceptable polymorph, prodrug, salt,stereoisomer, solvate, hydrate, or clathrate thereof, are alsoencompassed by the invention. Individual dosage forms of the inventionmay be suitable for oral, mucosal (including sublingual, buccal, rectal,nasal, or vaginal), parenteral (including subcutaneous, intramuscular,bolus injection, intraarterial, or intravenous), transdermal, or topicaladministration.

Pharmaceutical compositions and dosage forms of the invention compriseclofarabine, or a pharmaceutically acceptable prodrug, polymorph, salt,stereoisomer, solvate, hydrate, or clathrate thereof. Pharmaceuticalcompositions and dosage forms of the invention typically also compriseone or more pharmaceutically acceptable excipients.

A particular pharmaceutical composition encompassed by this embodimentcomprises clofarabine, or a pharmaceutically acceptable polymorph,prodrug, salt, solvate, hydrate, or clathrate thereof, and at least oneadditional therapeutic agent. Examples of additional therapeutic agentsinclude, but are not limited to, those listed above in section 4.2.

Single unit dosage forms of the invention are suitable for oral, mucosal(e.g., nasal, sublingual, vaginal, buccal, or rectal), parenteral (e.g.,subcutaneous, intravenous, bolus injection, intramuscular, orintraarterial), or transdermal administration to a patient. Examples ofdosage forms include, but are not limited to: tablets; caplets;capsules, such as soft elastic gelatin capsules; cachets; troches;lozenges; dispersions; suppositories; ointments; cataplasms (poultices);pastes; powders; dressings; creams; plasters; solutions; patches;aerosols (e.g., nasal sprays or inhalers); gels; liquid dosage formssuitable for oral or mucosal administration to a patient, includingsuspensions (e.g., aqueous or non-aqueous liquid suspensions,oil-in-water emulsions, or a water-in-oil liquid emulsions), solutions,and elixirs; liquid dosage forms suitable for parenteral administrationto a patient; and sterile solids (e.g., crystalline or amorphous solids)that can be reconstituted to provide liquid dosage forms suitable forparenteral administration to a patient.

The composition, shape, and type of dosage forms of the invention willtypically vary depending on their use. For example, a dosage form usedin the acute treatment of a disease or a related disease may containlarger amounts of one or more of the active ingredients it comprisesthan a dosage form used in the chronic treatment of the same disease.Similarly, a parenteral dosage form may contain smaller amounts of oneor more of the active ingredients it comprises than an oral dosage formused to treat the same disease or disorder. These and other ways inwhich specific dosage forms encompassed by this invention will vary fromone another will be readily apparent to those skilled in the art. See,e.g., Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing,Easton Pa. (1990).

Typical pharmaceutical compositions and dosage forms comprise one ormore carriers, excipients or diluents. Suitable excipients are wellknown to those skilled in the art of pharmacy, and non-limiting examplesof suitable excipients are provided herein. Whether a particularexcipient is suitable for incorporation into a pharmaceuticalcomposition or dosage form depends on a variety of factors well known inthe art including, but not limited to, the way in which the dosage formwill be administered to a patient. For example, oral dosage forms suchas tablets may contain excipients not suited for use in parenteraldosage forms. The suitability of a particular excipient may also dependon the specific active ingredients in the dosage form.

This invention further encompasses anhydrous pharmaceutical compositionsand dosage forms comprising active ingredients, since water canfacilitate the degradation of some compounds. For example, the additionof water (e.g., 5%) is widely accepted in the pharmaceutical arts as ameans of simulating long-term storage in order to determinecharacteristics such as shelf-life or the stability of formulations overtime. See, e.g., fens T. Carstensen, Drug Stability: Principles &Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp. 379-80. In effect,water and heat accelerate the decomposition of some compounds. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment, and use of formulations.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. Pharmaceutical compositionsand dosage forms that comprise lactose and at least one activeingredient that comprises a primary or secondary amine are preferablyanhydrous if substantial contact with moisture and/or humidity duringmanufacturing, packaging, and/or storage is expected.

An anhydrous pharmaceutical composition should be prepared and storedsuch that its anhydrous nature is maintained. Accordingly, anhydrouscompositions are preferably packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g. vials),blister packs, and strip packs.

The invention further encompasses pharmaceutical compositions and dosageforms that comprise one or more compounds that reduce the rate by whichan active ingredient will decompose. Such compounds, which are referredto herein as “stabilizers,” include, but are not limited to,antioxidants such as ascorbic acid, pH buffers, or salt buffers.

Like the amounts and types of excipients, the amounts and specific typesof active ingredients in a dosage form may differ depending on factorssuch as, but not limited to, the route by which it is to be administeredto patients. However, typical dosage forms of the invention compriseclofarabine, or a pharmaceutically acceptable salt, solvate, clathrate,hydrate, polymorph or prodrug thereof lie within the range of from 5mg/kg to about 75 mg/kg per day, more specifically, between about 20mg/kg and about 60 mg/kg per day, most specifically between about 40mg/kg and 50 mg/kg per day.

4.4.1 Oral Dosage Forms

Pharmaceutical compositions of the invention that are suitable for oraladministration can be presented as discrete dosage forms, such as, butare not limited to, tablets (e.g., chewable tablets), caplets, capsules,and liquids (e.g., flavored syrups). Such dosage forms containpredetermined amounts of active ingredients, and may be prepared bymethods of pharmacy well known to those skilled in the art. Seegenerally, Remington's Pharmaceutical Sciences, 18th ed., MackPublishing, Easton Pa. (1990).

Typical oral dosage forms of the invention are prepared by combining theactive ingredient(s) in an intimate admixture with at least oneexcipient according to conventional pharmaceutical compoundingtechniques. Excipients can take a wide variety of forms depending on theform of preparation desired for administration. For example, excipientssuitable for use in oral liquid or aerosol dosage forms include, but arenot limited to, water, glycols, oils, alcohols, flavoring agents,preservatives, and coloring agents. Examples of excipients suitable foruse in solid oral dosage forms (e.g., powders, tablets, capsules, andcaplets) include, but are not limited to, starches, sugars,micro-crystalline cellulose, diluents, granulating agents, lubricants,binders, and disintegrating agents.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit forms, in which case solidexcipients are employed. If desired, tablets can be coated by standardaqueous or nonaqueous techniques. Such dosage forms can be prepared byany of the methods of pharmacy. In general, pharmaceutical compositionsand dosage forms are prepared by uniformly and intimately admixing theactive ingredients with liquid carriers, finely divided solid carriers,or both, and then shaping the product into the desired presentation ifnecessary.

For example, a tablet can be prepared by compression or molding.Compressed tablets can be prepared by compressing in a suitable machinethe active ingredients in a free-flowing form such as powder orgranules, optionally mixed with an excipient. Molded tablets can be madeby molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

Examples of excipients that can be used in oral dosage forms of theinvention include, but are not limited to, binders, fillers,disintegrants, and lubricants. Binders suitable for use inpharmaceutical compositions and dosage forms include, but are notlimited to, corn starch, potato starch, or other starches, gelatin,natural and synthetic gums such as acacia, sodium alginate, alginicacid, other alginates, powdered tragacanth, guar gum, cellulose and itsderivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropylmethyl cellulose, (e.g., Nos. 2208, 2906, 2910), microcrystallinecellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositionsand dosage forms disclosed herein include, but are not limited to, talc,calcium carbonate (e.g. granules or powder), microcrystalline cellulose,powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol,starch, pre-gelatinized starch, and mixtures thereof. The binder orfiller in pharmaceutical compositions of the invention is typicallypresent in from about 50 to about 99 weight percent of thepharmaceutical composition or dosage form.

Suitable forms of microcrystalline cellulose include, but are notlimited to, the materials sold as AVICEL-PH-101, AVICEL-PH-103 AVICELRC-581, AVICEL-PH-105 (available from FMC Corporation, American ViscoseDivision, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. Anspecific binder is a mixture of microcrystalline cellulose and sodiumcarboxymethyl cellulose sold as AVICEL RC-581. Suitable anhydrous or lowmoisture excipients or additives include AVICEL-PH-103™ and Starch 1500LM.

Disintegrants are used in the compositions of the invention to providetablets that disintegrate when exposed to an aqueous environment.Tablets that contain too much disintegrant may disintegrate in storage,while those that contain too little may not disintegrate at a desiredrate or under the desired conditions. Thus, a sufficient amount ofdisintegrant that is neither too much nor too little to detrimentallyalter the release of the active ingredients should be used to form solidoral dosage forms of the invention. The amount of disintegrant usedvaries based upon the type of formulation, and is readily discernible tothose of ordinary skill in the art. Typical pharmaceutical compositionscomprise from about 0.5 to about 15 weight percent of disintegrant,specifically from about 1 to about 5 weight percent of disintegrant.

Disintegrants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, agar-agar,alginic acid, calcium carbonate, microcrystalline cellulose,croscarmellose sodium, crospovidone, polacrilin potassium, sodium starchglycolate, potato or tapioca starch, pre-gelatinized starch, otherstarches, clays, other algins, other celluloses, gums, and mixturesthereof.

Lubricants that can be used in pharmaceutical compositions and dosageforms of the invention include, but are not limited to, calciumstearate, magnesium stearate, mineral oil, light mineral oil, glycerin,sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid,sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanutoil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, andsoybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, andmixtures thereof. Additional lubricants include, for example, a syloidsilica gel (AEROSIL 200, manufactured by W. R. Grace Co. of Baltimore,Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co.of Plano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold byCabot Co. of Boston, Mass.), and mixtures thereof. If used at all,lubricants are typically used in an amount of less than about 1 weightpercent of the pharmaceutical compositions or dosage forms into whichthey are incorporated.

4.4.2 Delayed Release Dosage Forms

Active ingredients of the invention can be administered by controlledrelease means or by delivery devices that are well known to those ofordinary skill in the art. Examples include, but are not limited to,those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809;3,598,123; and 4,008,719, 5,674,533, 5,059,595, 5,591,767, 5,120,548,5,073,543, 5,639,476, 5,354,556, and 5,733,566, each of which isincorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

All controlled-release pharmaceutical products have a common goal ofimproving drug therapy over that achieved by their non-controlledcounterparts. Ideally, the use of an optimally designedcontrolled-release preparation in medical treatment is characterized bya minimum of drug substance being employed to cure or control thecondition in a minimum amount of time. Advantages of controlled-releaseformulations include extended activity of the drug, reduced dosagefrequency, and increased patient compliance. In addition,controlled-release formulations can be used to affect the time of onsetof action or other characteristics, such as blood levels of the drug,and can thus affect the occurrence of side (e.g., adverse) effects.

Most controlled-release formulations are designed to initially releasean amount of drug (active ingredient) that promptly produces the desiredtherapeutic effect, and gradually and continually release of otheramounts of drug to maintain this level of therapeutic or prophylacticeffect over an extended period of time. In order to maintain thisconstant level of drug in the body, the drug must be released from thedosage form at a rate that will replace the amount of drug beingmetabolized and excreted from the body. Controlled-release of an activeingredient can be stimulated by various conditions including, but notlimited to, pH, temperature, enzymes, water, or other physiologicalconditions or compounds.

4.4.3 Parenteral Dosage Forms

Parenteral dosage forms can be administered to patients by variousroutes including, but not limited to, subcutaneous, intravenous(including bolus injection), intramuscular, and intraarterial. Becausetheir administration typically bypasses patients' natural defensesagainst contaminants, parenteral dosage forms are preferably sterile orcapable of being sterilized prior to administration to a patient.Examples of parenteral dosage forms include, but are not limited to,solutions ready for injection, dry products ready to be dissolved orsuspended in a pharmaceutically acceptable vehicle for injection(reconstitutable powders), suspensions ready for injection, andemulsions.

Suitable vehicles that can be used to provide parenteral dosage forms ofthe invention are well known to those skilled in the art. Examplesinclude, but are not limited to: Water for Injection USP; aqueousvehicles such as, but not limited to, Sodium Chloride Injection,Ringer's Injection, Dextrose Injection, Dextrose and Sodium ChlorideInjection, and Lactated Ringer's Injection; water-miscible vehicles suchas, but not limited to, ethyl alcohol, polyethylene glycol, andpolypropylene glycol; and non-aqueous vehicles such as, but not limitedto, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate,isopropyl myristate, and benzyl benzoate.

Compounds that increase the solubility of one or more of the activeingredients disclosed herein can also be incorporated into theparenteral dosage forms of the invention.

4.4.4 Transdermal and Topical Dosage Forms

Transdermal and topical dosage forms of the invention include, but arenot limited to, creams, lotions, ointments, gels, solutions, emulsions,suspensions, or other forms known to one of skill in the art. See, e.g.,Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, EastonPa. (1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed.,Lea & Febiger, Philadelphia (1985). Transdermal dosage forms include“reservoir type” or “matrix type” patches, which can be applied to theskin and worn for a specific period of time to permit the penetration ofa desired amount of active ingredients.

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide transdermal and topical dosage formsencompassed by this invention are well known to those skilled in thepharmaceutical arts, and depend on the particular tissue to which agiven pharmaceutical composition or dosage form will be applied. Withthat fact in mind, typical excipients include, but are not limited to,water, acetone, ethanol, ethylene glycol, propylene glycol,butane-1,3-diol, isopropyl myristate, isopropyl palmitate, mineral oil,and mixtures thereof to form lotions, tinctures, creams, emulsions, gelsor ointments, which are non-toxic and pharmaceutically acceptable.Moisturizers or humectants can also be added to pharmaceuticalcompositions and dosage forms if desired. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 118th eds., Mack Publishing, Easton Pa. (1990).

Depending on the specific tissue to be treated, additional componentsmay be used prior to, in conjunction with, or subsequent to treatmentwith active ingredients of the invention. For example, penetrationenhancers can be used to assist in delivering the active ingredients tothe tissue. Suitable penetration enhancers include, but are not limitedto: acetone, various alcohols such as ethanol, oleyl, andtetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethylacetamide; dimethyl formamide; polyethylene glycol; pyrrolidones such aspolyvinylpyrrolidone; Kollidon grades Povidone, Polyvidone); urea; andvarious water-soluble or insoluble sugar esters such as Tween 80(polysorbate 80) and Span 60 (sorbitan monostearate).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, mayalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

4.4.5 Mucosal Dosage Forms

Mucosal dosage forms of the invention include, but are not limited to,ophthalmic solutions, sprays and aerosols, or other forms known to oneof skill in the art. See, e.g., Remington's Pharmaceutical Sciences,18th eds., Mack Publishing, Easton Pa. (1990); and Introduction toPharmaceutical Dosage Forms, 4th ed., Lea & Febiger, Philadelphia(1985). Dosage forms suitable for treating mucosal tissues within theoral cavity can be formulated as mouthwashes or as oral gels. In oneembodiment, the aerosol comprises a carrier. In another embodiment, theaerosol is carrier free.

Clofarabine may also be administered directly to the lung by inhalation.For administration by inhalation, clofarabine can be convenientlydelivered to the lung by a number of different devices. For example, aMetered Dose Inhaler (“MDI”) which utilizes canisters that contain asuitable low boiling propellant, e.g. dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas can be used to deliver a compound of formula Idirectly to the lung. MDI devices are available from a number ofsuppliers such as 3M Corporation, Aventis, Boehringer Ingleheim, ForestLaboratories, Glaxo-Wellcome, Schering Plough and Vectura.

Alternatively, a Dry Powder Inhaler (DPI) device can be used toadminister a compound of formula I to the lung (See, e.g., Raleigh etal., Proc. Amer. Assoc. Cancer Research Annual Meeting, 1999, 40, 397,which is herein incorporated by reference). DPI devices typically use amechanism such as a burst of gas to create a cloud of dry powder insidea container, which can then be inhaled by the patient. DPI devices arealso well known in the art and can be purchased from a number of vendorswhich include, for example, Fisons, Glaxo-Wellcome, Inhale TherapeuticSystems, ML Laboratories, Qdose and Vectura. A popular variation is themultiple dose DPI (“MDDPI”) system, which allows for the delivery ofmore than one therapeutic dose. MDDPI devices are available fromcompanies such as AstraZeneca, GlaxoWellcome, IVAX, Schering Plough,SkyePharma and Vectura. For example, capsules and cartridges of gelatinfor use in an inhaler or insufflator can be formulated containing apowder mix of the compound and a suitable powder base such as lactose orstarch for these systems.

Another type of device that can be used to deliver clofarabine to thelung is a liquid spray device supplied, for example, by AradigmCorporation. Liquid spray systems use extremely small nozzle holes toaerosolize liquid drug formulations that can then be directly inhaledinto the lung.

In a preferred embodiment, a nebulizer device is used to deliverclofarabine to the lung. Nebulizers create aerosols from liquid drugformulations by using, for example, ultrasonic energy to form fineparticles that can be readily inhaled (See e.g. Verschoyle et al.,British J Cancer, 1999, 80, Suppl 2, 96, which is herein incorporated byreference). Examples of nebulizers include devices supplied bySheffield/Systemic Pulmonary Delivery Ltd. (See, Armer et al., U.S. Pat.No. 5,954,047; van der Linden et al., U.S. Pat. No. 5,950,619; van derLinden et al., U.S. Pat. No. 5,970,974, which are herein incorporated byreference), Aventis and Batelle Pulmonary Therapeutics. Inhaled compoundof formula I, delivered by nebulizer devices, is currently underinvestigation as a treatment for aerodigestive cancer (Engelke et al.,Poster 342 at American Association of Cancer Research, San Francisco,Calif., Apr. 1-5, 2000) and lung cancer (Dahl et al., Poster 524 atAmerican Association of Cancer Research, San Francisco, Calif., Apr.1-5, 2000).

In a particularly preferred embodiment, an electrohydrodynamic (“EHD”)aerosol device is used to deliver clofarabine to the lung. EHD aerosoldevices use electrical energy to aerosolize liquid drug solutions orsuspensions (see e.g., Noakes et al., U.S. Pat. No. 4,765,539; Coffee,U.S. Pat. No. 4,962,885; Coffee, PCT Application, WO 94/12285; Coffee,PCT Application, WO 94/14543; Coffee, PCT Application, WO 95/26234,Coffee, PCT Application, WO 95/26235, Coffee, PCT Application, WO95/32807, which are herein incorporated by reference). Theelectrochemical properties of the compound of formula I formulation maybe important parameters to optimize when delivering this drug to thelung with an EHD aerosol device and such optimization is routinelyperformed by one of skill in the art. EHD aerosol devices may moreefficiently delivery drugs to the lung than existing pulmonary deliverytechnologies. Other methods of intra-pulmonary delivery of clofarabinewill be known to the skilled artisan and are within the scope of theinvention.

Liquid drug formulations suitable for use with nebulizers and liquidspray devices and EHD aerosol devices will typically include a compoundof formula I with a pharmaceutically acceptable carrier. Preferably, thepharmaceutically acceptable carrier is a liquid such as alcohol, water,polyethylene glycol or a perfluorocarbon. Optionally, another materialmay be added to alter the aerosol properties of the solution orsuspension of clofarabine. Preferably, this material is liquid such asan alcohol, glycol, polyglycol or a fatty acid. Other methods offormulating liquid drug solutions or suspension suitable for use inaerosol devices are known to those of skill in the art (See, e.g.,Biesalski, U.S. Pat. Nos. 5,112,598; Biesalski, 5,556,611, which areherein incorporated by reference) A compound of formula I can also beformulated in rectal or vaginal compositions such as suppositories orretention enemas, e.g., containing conventional suppository bases suchas cocoa butter or other glycerides.

In addition to the formulations described previously, clofarabine canalso be formulated as a depot preparation. Such long acting formulationscan be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds can be formulated with suitable polymeric or hydrophobicmaterials (for example, as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

Alternatively, other pharmaceutical delivery systems can be employed.Liposomes and emulsions are well known examples of delivery vehiclesthat can be used to deliver clofarabine. Certain organic solvents suchas dimethylsulfoxide can also be employed, although usually at the costof greater toxicity. A compound of formula I can also be delivered in acontrolled release system. In one embodiment, a pump can be used(Sefton, CRC Crit. Ref Biomed Eng., 1987, 14, 201; Buchwald et al.,Surgery, 1980, 88, 507; Saudek et al., N. Engl. J. Med, 1989, 321, 574).In another embodiment, polymeric materials can be used (see MedicalApplications of Controlled Release, Langer and Wise (eds.), CRC Pres.,Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug ProductDesign and Performance, Smolen and Ball (eds.), Wiley, New York (1984);Ranger and Peppas, 3 Macromol. Sci. Rev. Macromol. Chem., 1983, 23, 61;see also Levy et al., Science 1985, 228, 190; During et al., Arm.Neurol., 1989, 25, 351; Howard et al., 1989, J. Neurosurg. 71, 105). Inyet another embodiment, a controlled-release system can be placed inproximity of the target of the compounds of the invention, e.g., thelung, thus requiring only a fraction of the systemic dose (see, e.g.,Goodson, in Medical Applications of Controlled Release, supra, vol. 2,pp. 115 (1984)). Other controlled-release system can be used (see e.g.Langer, Science, 1990, 249, 1527).

Suitable excipients (e.g., carriers and diluents) and other materialsthat can be used to provide mucosal dosage forms encompassed by thisinvention are well known to those skilled in the pharmaceutical arts,and depend on the particular site or method which a given pharmaceuticalcomposition or dosage form will be administered. With that fact in mind,typical excipients include, but are not limited to, water, ethanol,ethylene glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,isopropyl palmitate, mineral oil, and mixtures thereof, which arenon-toxic and pharmaceutically acceptable. Examples of such additionalingredients are well known in the art. See, e.g., Remington'sPharmaceutical Sciences, 18th eds., Mack Publishing, Easton Pa. (1990).

The pH of a pharmaceutical composition or dosage form, or of the tissueto which the pharmaceutical composition or dosage form is applied, canalso be adjusted to improve delivery of one or more active ingredients.Similarly, the polarity of a solvent carrier, its ionic strength, ortonicity can be adjusted to improve delivery. Compounds such asstearates can also be added to pharmaceutical compositions or dosageforms to advantageously alter the hydrophilicity or lipophilicity of oneor more active ingredients so as to improve delivery. In this regard,stearates can serve as a lipid vehicle for the formulation, as anemulsifying agent or surfactant, and as a delivery-enhancing orpenetration-enhancing agent. Different salts, hydrates or solvates ofthe active ingredients can be used to further adjust the properties ofthe resulting composition.

This and other novel and unexpected advantages of the invention arefurther illustrated by the following non-limiting examples.

5. EXAMPLES 5.1 Example 1 Parenteral Dosage Formulation

Clofarabine, 9.86 g, is wetted/partially dissolved with 600 mL of a 9:1mixture of tertiary butanol and Water for Injection USP which ispre-cooled to 5° C. Once the drug powder is completely wetted,dissolution is completed by the addition of 600 mL of a 1:9 mixture oftertiary butanol and Water for Injection and 766 mL of a 1:1 mixture oftertiary butanol and Water for Injection which likewise is pre-cooled to5° C. thereby making the final solution a 1:1 mixture. The dissolutionis carried out under protection from light.

The solution formed above is promptly lyophilized in a Virtis INOTOPlyophilizer at −16° C. under light protectant conditions over a periodof 48 hours. The resultant lyophilized product (lyophile) is thenfurther dried at 15° C. under high vacuum for 48 hours. No detectabledegradation of the drug is observed during these procedures. Thelyophile is packaged under sterile conditions into 30 mL vials, eachcontaining 50 mg of drug, 50 mg of mannitol and sodium hydroxide toadjust the pH to 7.7 and standard excess to allow forvial/needle/syringe loss.

The lyophile is reconstituted with 2 mL of Water for Injection USP,which typically will be supplied with the drug in a separate vial, toachieve a final drug concentration of 25 mg/mL.

5.2 Example 2:25 Mg Dosage Capsule

Table 1 illustrates a batch formulation and a single dose unitformulation containing 25 mg of Clofarabine.

TABLE 1 Formulation for 25 mg tablet Quantity Quantity Material Percentby Weight (mg/tablet) (kg/batch) Clofarabine  40% 25.00 20.00Microcrystalline 53.5%  33.44 26.75 Cellulose, NF Pluronic F-68 4.0%2.50 2.00 Surfactant Croscarmellose 2.0% 1.25 1.00 Sodium Type A, NFMagnesium Stearate, 0.5% 0.3125 0.25 NF Total 100.0%  62.50 mg 50.00 kg

The microcrystalline cellulose, croscarmellose sodium, and Clofarabinecomponents are passed through a #30 mesh screen (about 430μ to about655μ). The Pluronic F-68® (manufactured by JRH Biosciences, Inc. ofLenexa, Kans.) surfactant is passed through a #20 mesh screen (about457μ to about 1041μ). The Pluronic F-68® surfactant and 0.5 kgs ofcroscarmellose sodium are loaded into a 16 qt. twin shell tumble blenderand are mixed for about 5 minutes. The mix is then transferred to a 3cubic foot twin shell tumble blender where the microcrystallinecellulose is added and blended for about 5 minutes. The thalidomide isadded and blended for an additional 25 minutes. This pre-blend is passedthrough a roller compactor with a hammer mill attached at the dischargeof the roller compactor and moved back to the tumble blender. Theremaining croscarmellose sodium and magnesium stearate is added to thetumble blender and blended for about 3 minutes. The final mixture iscompressed on a rotary tablet press with 62.5 mg per tablet (800,000tablet batch size).

5.3 Example 3 50 Mg Dosage Capsule

Table 2 illustrates a batch formulation and a single dose unitformulation containing 50 mg of Clofarabine.

TABLE 2 Formulation for 50 mg tablet Quantity Quantity Material Percentby Weight (mg/tablet) (kg/batch) Clofarabine  40% 50.00 20.00Microcrystalline 53.5%  66.875 26.75 Cellulose, NF Pluronic F-68 4.0%5.00 2.00 Surfactant Croscarmellose 2.0% 2.50 1.00 Sodium Type A, NFMagnesium Stearate, 0.5% 0.625 0.25 NF Total 100.0%  125.00 mg 50.00 kg

The microcrystalline cellulose, croscarmellose sodium, and Clofarabinecomponents are passed through a #30 mesh screen (about 430μ to about655μ). The Pluronic F-68® (manufactured by JRH Biosciences, Inc. ofLenexa, Kans.) surfactant is passed through a #20 mesh screen (about457μ to about 1041μ). The Pluronic F-680® surfactant and 0.5 kgs ofcroscarmellose sodium are loaded into a 16 qt. twin shell tumble blenderand are mixed for about 5 minutes. The mix is then transferred to a 3cubic foot twin shell tumble blender where the microcrystallinecellulose is added and blended for about 5 minutes. The thalidomide isadded and blended for an additional 25 minutes. This pre-blend is passedthrough a roller compactor with a hammer mill attached at the dischargeof the roller compactor and moved back to the tumble blender. Theremaining croscarmellose sodium and magnesium stearate is added to thetumble blender and blended for about 3 minutes. The final mixture iscompressed on a rotary tablet press with 125 mg per tablet (400,000tablet batch size).

5.4 Example 4 200 Mg Dosage Capsule

Table 3 illustrates a batch formulation and single dosage formulationfor a 200 mg Clofarabine single dose unit, i.e., about 40 percent byweight.

TABLE 3 Formulation for 200 mg capsule Quantity Quantity MaterialPercent By Weigh (mg/tablet) (kg/batch) Clofarabine 40.0%  200 mg 16.80kg Pregelatinized Corn 9.5% 297.5 mg 24.99 kg Starch, NF5 MagnesiumStearate 0.5% 2.5 mg  0.21 kg Total 100.0%  500 mg 42.00 kg

The pregelatinized corn starch (SPRESS B-820) and3-[2-(3′-methyl-biphen-4-yloxy)-acetylamino]-benzoic acid components arepassed through a 710 μm screen and then are loaded into a DiffusionMixer with a baffle insert and blended for 15 minutes. The magnesiumstearate is passed through a 210 μL m screen and is added to theDiffusion Mixer. The blend is then encapsulated in a size #0 capsule,500 mg per capsule (8400 capsule batch size) using a Dosator typecapsule filling machine.

5.5 Example 5 100 Mg Oral Dosage Form

Table 4 illustrates a batch formulation and a single dose unitformulation containing 100 mg of Clofarabine.

TABLE 4 Formulation for 100 mg tablet Quantity Quantity Material Percentby Weight (mg/tablet) (kg/batch) Clofarabine  40% 100.00 20.00Microcrystalline 53.5%  133.75 26.75 Cellulose, NF Pluronic F-68 4.0%10.00 2.00 Surfactant Croscarmellose 2.0% 5.00 1.00 Sodium Type A, NFMagnesium Stearate, 0.5% 1.25 0.25 NF Total 100.0%  250.00 mg 50.00 kg

The microcrystalline cellulose, croscarmellose sodium, and Clofarabinecomponents are passed through a #30 mesh screen (about 430μ to about655μ). The Pluronic F-68® (manufactured by JRH Biosciences, Inc. ofLenexa, Kans.) surfactant is passed through a #20 mesh screen (about457μ to about 1041μ). The Pluronic F-68® surfactant and 0.5 kgs ofcroscarmellose sodium are loaded into a 16 qt. twin shell tumble blenderand are mixed for about 5 minutes. The mix is then transferred to a 3cubic foot twin shell tumble blender where the microcrystallinecellulose is added and blended for about 5 minutes. The thalidomide isadded and blended for an additional 25 minutes. This pre-blend is passedthrough a roller compactor with a hammer mill attached at the dischargeof the roller compactor and moved back to the tumble blender. Theremaining croscarmellose sodium and magnesium stearate is added to thetumble blender and blended for about 3 minutes. The final mixture iscompressed on a rotary tablet press with 250 mg per tablet (200,000tablet batch size).

5.6 Example 6 Aerosol Dosage Form

A concentrate is prepared by combining Clofarabine, and a 12.6 kgportion of the trichloromonofluoromethane in a sealed stainless steelvessel equipped with a high shear mixer. Mixing is carried out for about20 minutes. The bulk suspension is then prepared in the sealed vessel bycombining the concentrate with the balance of the propellants in a bulkproduct tank that is temperature controlled to 21° to 27° C. andpressure controlled to 2.8 to 4.0 BAR. 17 ml aerosol containers whichhave a metered valve which is designed to provide 100 inhalations of thecomposition of the invention. Each container is provided with thefollowing:

Clofarabine 0.0141 g trichloromonofluoromethane 1.6939 gdichlorodifluoromethane 3.7154 g dichlorotetrafluoroethane 1.5766 gtotal 7.0000 g

While the invention has been described with respect to the particularembodiments, it will be apparent to those skilled in the art thatvarious changes and modifications may be made without departing from thespirit and scope of the invention as defined in the claims. Suchmodifications are also intended to fall within the scope of the appendedclaims.

1. A method of treating multiple sclerosis which comprises administering to a patient from about 1.25 mg/kg/day to about 80 mg/kg/day of clofarabine or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, clathrate, prodrug or metabolite thereof.
 2. The method of claim 1 which comprises administering from about 50 mg/kg/day to about 75 mg/kg/day of clofarabine or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, clathrate, prodrug or metabolite thereof.
 3. The method of claim 1 which comprises administering from about 20 mg/kg/day to about 60 mg/kg/day of clofarabine or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, clathrate, prodrug or metabolite thereof.
 4. The method of claim 1 which comprises administering from about 40 mg/kg/day to about 50 mg/kg/day of clofarabine or a pharmaceutically acceptable salt, stereoisomer, solvate, hydrate, clathrate, prodrug or metabolite thereof.
 5. The method of claim 1 wherein the therapeutically or prophylactively effective amount of clofarabine is administered parenterally.
 6. The method of claim 1 wherein the therapeutically or prophylactively effective amount of clofarabine is administered orally.
 7. A method of treating psoriasis which comprises administering to a patient having psoriasis a therapeutically effective amount of clofarabine or a pharmaceutically acceptable salt, stereoisomer or solvate thereof.
 8. The method of claim 7, wherein clofarabine or a pharmaceutically acceptable salt, stereoisomer or solvate thereof is administered in a tablet.
 9. The method of claim 8, wherein the tablet comprises about 25 mg of clofarabine.
 10. The method of claim 8, wherein the tablet comprises about 50 mg of clofarabine.
 11. The method of claim 8, wherein the tablet comprises about 100 mg of clofarabine.
 12. The method of claim 8, wherein the tablet comprises about 200 mg of clofarabine.
 13. The method of claim 7 wherein the therapeutically or prophylactically effective amount of clofarabine is from about 5 mg/kg/day to about 75 mg/kg/day.
 14. The method of claim 7 wherein the therapeutically or prophylactically effective amount of clofarabine is from about 20 mg/kg/day to about 60 mg/kg/day.
 15. The method of claim 7 wherein the therapeutically or prophylactically effective amount of clofarabine is from about 40 mg/kg/day to about 50 mg/kg/day.
 16. The method of claim 7 further comprising the administration of an additional therapeutic agent.
 17. The method of claim 16 wherein the additional therapeutic agent is an antibiotic, an antiemetic agent, an antidepressant, and antifungal agent, an anti-inflammatory agent, an antiviral agent, an immunomodulatory agent, a β-interferon, an alkylating agent, a hormone or a cytokine.
 18. The method of claim 7, wherein clofarabine is administered as a pharmaceutically acceptable salt.
 19. The method of claim 7, wherein clofarabine is administered as a free base.
 20. The method of claim 17, wherein the immunomodulatory agent is selected from the group consisting of methothrexate, leflunomide, cyclophosphamide, cytoxan, lmmuran, cyclosporine A, minocycline, azathioprine, antibiotics, tacrolimus, methylprednisolone, corticosteroids, steriods, mycophenolate mofetil, rapamycin, sirolimus, mizoribine, deoxyspergualin, brequinar, malononitriloamindes, T cell receptor modulators, and cytokine receptor modulators. 